Mantle
cell lymphoma (MCL), a subtype of non-Hodgkin lymphoma (NHL), is diagnosed in
about 4200 people per year in the United States.1 MCL often
progresses quickly and most patients require immediate treatment. But MCL is
incurable with current therapeutic options, which means effective approaches
for relapsed/refractory disease are in demand.

Treatment
with ibrutinib, a bruton tyrosine kinase (BTK) inhibitor, is the current
standard approach for relapsed/refractory MCL. But patients who progress
following this treatment have an overall survival rate of just 6 to 10 months.2-4
Very few of these patients are candidates for stem cell transplantation. “There
are no good treatment options for MCL after failing BTK inhibitors,” said Julio
Chavez, MD, who researches and treats lymphoma at Moffitt Cancer Center, Tampa,
Florida.

Enter chimeric
antigen receptor T-cell (CAR-T) immunotherapy — or clinical investigations of
it in MCL, at least. This approach is being increasingly explored to treat
aggressive subtypes of NHL. Given the poor prognosis of patients with
relapsed/refractory MCL, investigating whether CAR-T therapy could improve
survival times is logical.

The
phase 2 ZUMA-2 study sought to do just that. And, interestingly, there was no
phase 1 study of ZUMA-1 — the dose of KTE-X19 being investigated in the phase 2
trial was determined on the basis of studies of axicabtagene ciloleucel in
patients with large B-cell lymphoma and of KTE-X19 in patients with acute
lymphoblastic leukemia.

KTE-X19
is a CAR-T that targets CD19 cells.5 A multicenter group of
researchers, led by Michael Wang, MD, from the MD Anderson Cancer Center,
Houston, Texas, enrolled patients with relapsed/refractory MCL whose disease
had progressed after treatment with BTK inhibitors.

After
undergoing leukapheresis and treatment with conditioning therapy, patients
received a single infusion of KTE-X19 at a dose of 2×106 CAR T cells
per kilogram of body weight. The protocol also allowed for bridging therapy
with dexamethasone, ibrutinib, or acalabrutinib. The median time from
leukapheresis to the delivery of KTE-X19 at the trial site was 16 days.

As of
May 30, 2018, 28 patients had received KTE-X19 and there were follow-up data
available of at least 1 year for that small group (median follow-up, 13.2 months),
according to information presented at the Transplantation & Cellular
Therapy Meetings of the American Society for Transplantation and Cellular
Therapy and Center for International Blood and Marrow Transplant Research.
These data were presented in February 2020 at that meeting.

Since then, updated data and trial details were presented in an article published in the New England Journal of Medicine on April 2, 2020.6 For that update, enrolled patients had to have received 5 or fewer prior therapies, 1 of which was required to be a BTK inhibitor (BTKi) — but the BTKi (either ibrutinib or acalabrutinib) was not required to be the last line of therapy before trial entry, and patients were not required to have disease that was refractory to BTK inhibition (it was determined that 88% of the treated patients had disease that was considered to be refractory to BTK inhibitor therapy). Other previous therapies still must have included anthracycline- or bendamustine-containing chemotherapy and an anti-CD20 monoclonal antibody.

Objective
response rate (which includes both complete and partial response) was the focus
of the preliminary studies, and the study update. Would CAR-T therapy renew the
body’s fight against cancer, even at this late stage of the disease? For most
patients who had at least 7 months of follow-up, the answer was: likely yes. The
authors wrote in NEJM that “among the
protocol-specified 60 patients with relapsed or refractory mantle-cell
lymphoma, KTE-X19 resulted in an objective response in 93% of the patients and
in a complete response in 67%.”6

Based on this complete response rate, the US Food and Drug Administration awarded KTE-X19 Priority Review in February 2020.7 It had already received a Breakthrough Therapy Designation from the agency. The Prescription Drug User Fee Act (PDUFA), or target action date for a final decision by the FDA, is anticipated to be on or before August 10, 2020.

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